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Cellular Regulations by RB-Associated Proteins

RB 相关蛋白的细胞调节

基本信息

批准号：
6913719
负责人：
Robert Chiu
金额：
$ 24.02万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-04-01 至 2007-06-30
项目状态：
已结题

项目摘要

EXCEED THE SPACE PROVIDED. Since the first identification of the role of CypA in CsA-induced immunosuppression, its cellular function becomes only slowly unraveled. Recently, different aspects of biological functions of CypA have emerged that provide an invaluable means for further understanding the function of CypA in cellular regulation. Since our first identification of CypA as an Rb associated protein, we have attempted further characterization of cellular function of CypA. Our recent data show that shRNA for targeting CypA have resulted in several altered phenotypes in P19 EC cells and osteosarcoma cell line, U2OS. The altered phenotypes: 1) have increased cell growth rates and have lost their potential for retinoic acid (RA)-induced neuronal differentiation; 2) have lost their response to both retinoic acid (RA) and bone morphogenetic protein (BMP)- 4 (RA/BMP4)-induced apoptosis; 3) have a disorganizing F-actin and reduced cell migratory activity and transformation capacity in CypA knocked-down U2OS cells. These data suggest that CypA is involved in multiple pathways in cellular regulation. These data have led us hypothesize that CypA acts as a chaperon to change the expression of a set of genes that play pivotal roles in determining cell fate, signaling and morphology. To test this hypothesis, we propose the following specific aims: 1. Elucidate the mechanism by which CypA is involved in the effect of RA/BMP-4-induced programmed cell death of P19 EC cells; 2. Elucidate the mechanism by which CypA affects the processing of RA-induced neuronal differentiation of P19 EC Cells; 3. Study the role of CypA for F-actin assembly in U2OS, and the possibility of applying the down-regulated CypA to cancer therapy. If CypA is proven to be an important in modulating the expression of a set of genes such as msxl and gasl, it can aid us further understanding the CypA network in regulation of cellular functions. In addition, a close link between the inactivation of CypA and induction of DNA hypermethylation of Peg3 can also impact our knowledge in tumorigenesis. Lastly, CypA can be tremendously useful as a therapeutic target, since down-regulated CypA alters actin cytoskeleton, which leads to reduce tumor cells growth, transformation capacity, alteration of signaling, and sensitizing cells to chemotherapeutic agents. * The role of CypA is involved in multiple pathways in cellular regulations. It can be useful as a therapeutic target as it can switch on-off a regulatory protein leading cancer cells to death. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。自从第一次发现CypA在CsA诱导的免疫抑制中的作用以来，其细胞功能只是慢慢地解开。最近，CypA生物学功能的不同方面已经出现，为进一步了解CypA在细胞调节中的功能提供了宝贵的手段。自从我们第一次鉴定CypA作为Rb相关蛋白以来，我们试图进一步表征CypA的细胞功能。我们最近的数据显示，靶向CypA的shRNA在P19 EC细胞和骨肉瘤细胞系U2 OS中导致了几种表型的改变。改变的表型：1）具有增加的细胞生长速率，并且已经失去了它们对视黄酸（RA）诱导的神经元分化的潜力; 2）已经失去了它们对视黄酸（RA）和骨形态发生蛋白（BMP）-4（RA/BMP 4）诱导的细胞凋亡的响应; 3）在CypA敲低的U2 OS细胞中具有混乱的F-肌动蛋白和降低的细胞迁移活性和转化能力。这些数据表明CypA参与细胞调节的多个途径。这些数据使我们假设CypA作为伴侣分子改变一组基因的表达，这些基因在决定细胞命运、信号传导和形态学方面发挥关键作用。为了验证这一假设，我们提出了以下具体目标：1。阐明CypA参与RA/BMP-4诱导P19 EC细胞程序性死亡的机制; 2.阐明CypA对RA诱导的P19 EC细胞神经元分化过程的影响机制; 3.研究CypA在U2 OS中F-actin组装中的作用，以及将下调的CypA应用于肿瘤治疗的可能性。如果CypA被证明在调控一组基因如msxl和gasl的表达中起重要作用，它可以帮助我们进一步了解CypA网络在细胞功能调控中的作用。此外，CypA的失活和诱导Peg 3的DNA超甲基化之间的密切联系也可能影响我们对肿瘤发生的认识。最后，CypA可以作为治疗靶点非常有用，因为下调的CypA改变肌动蛋白细胞骨架，这导致肿瘤细胞生长减少、转化能力降低、信号传导改变以及细胞对化疗剂敏感。* CypA的作用涉及细胞调节的多个途径。它可以用作治疗靶点，因为它可以打开-关闭导致癌细胞死亡的调节蛋白。性能现场=